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Hydrolytic biotransformation of the bumetanide ester prodrug DIMAEB to bumetanide by esterases in neonatal human and rat serum and neonatal rat brain : A new treatment strategy for neonatal seizures?
- Source :
- Epilepsia 62 (2021), Nr. 1
- Publication Year :
- 2021
- Publisher :
- Oxford [u.a.] : Wiley-Blackwell, 2021.
-
Abstract
- Objectives: The loop diuretic bumetanide has been proposed previously as an adjunct treatment for neonatal seizures because bumetanide is thought to potentiate the action of γ--aminobutyric acid (GABA)ergic drugs such as phenobarbital by preventing abnormal intracellular accumulation of chloride and the subsequent "GABA shift." However, a clinical trial in neonates failed to demonstrate such a synergistic effect of bumetanide, most likely because this drug only poorly penetrates into the brain. This prompted us to develop lipophilic prodrugs of bumetanide, such as the N,N-dimethylaminoethyl ester of bumetanide (DIMAEB), which rapidly enter the brain where they are hydrolyzed by esterases to the parent compound, as demonstrated previously by us in adult rodents. However, it is not known whether esterase activity in neonates is sufficient to hydrolyze ester prodrugs such as DIMAEB. Methods: In the present study, we examined whether esterases in neonatal serum of healthy term infants are capable of hydrolyzing DIMAEB to bumetanide and whether this activity is different from the serum of adults. Furthermore, to extrapolate the findings to brain tissue, we performed experiments with brain tissue and serum of neonatal and adult rats. Results: Serum from 1- to 2-day-old infants was capable of hydrolyzing DIMAEB to bumetanide at a rate similar to that of serum from adult individuals. Similarly, serum and brain tissue of neonatal rats rapidly hydrolyzed DIMAEB to bumetanide. Significance: These data provide a prerequisite for further evaluating the potential of bumetanide prodrugs as add-on therapy to phenobarbital and other antiseizure drugs as a new strategy for improving pharmacotherapy of neonatal seizures. © 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy
- Subjects :
- 0301 basic medicine
Drug
Male
Serum
medicine.drug_class
media_common.quotation_subject
phenobarbital
Pharmacology
Blood–brain barrier
03 medical and health sciences
0302 clinical medicine
Pharmacotherapy
BUM5
medicine
NKCC1
Animals
Humans
Prodrugs
ddc:610
Bumetanide
media_common
business.industry
Esterases
Infant, Newborn
Brain
Esters
ontogenesis
Loop diuretic
Prodrug
blood-brain barrier
carboxylesterase
Rats
030104 developmental biology
medicine.anatomical_structure
Neurology
Animals, Newborn
Phenobarbital
Female
Neurology (clinical)
Dewey Decimal Classification::600 | Technik::610 | Medizin, Gesundheit
business
030217 neurology & neurosurgery
Intracellular
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Epilepsia 62 (2021), Nr. 1
- Accession number :
- edsair.doi.dedup.....7adc06a21f5f186839f53abaf34ce308